The development of computation tools for the determination of energetically favorable binding sites in macromolecules, referred to as "docking", has been of considerable interest during the past decade. These tools have been introduced to assist structure-based drug design. The approaches fall into two main categories, namely, qualitative and quantitative methods. Qualitative methods are restricted primarily to calculations based on shape, complementarity and consist of finding the best fit between two shapes. A computer program called "Dock" exemplifies this approach and has been described in the paper authored by B. K. Shoichet and I. D. Kuntz entitled "Matching chemistry and shape in molecular docking", which appeared in Protein Engineering, 7:723-732, 1993. Quantitative methods are based primarily on energy calculations seeking to determine the global minimum energy of the ligand binding interaction with the protein target. This approach is described in the paper by P. A. Kollman entitled "Free energy calculations: applications to chemical and biochemical phenomena", published in Chem. Rev. 93:2395-2417, 1993. Hybrid methods also exist in the form of calculating interaction energy between a given protein and small molecular fragments which are then assembled based on shape, complementarity criteria to form new molecules. This approach is described in the paper by P. A. Goodford entitled "Computational procedure for determining energetically favorable binding sites on biologically important molecules", published in J. Med. Chem, 28:849-857, 1985. More recently, a successful prediction was achieved in describing the binding of .beta.-lactamase inhibitor protein with TEM-1 .beta.-lactamase by employing both quantitative and qualitative methods as well as a combination thereof. This approach is documented in the paper by N. Strynadka et al entitled "Molecular docking program successfully predict the binding of .beta.-lactamase inhibitory protein to TEM-1 .beta.-lactamase", published in Nature Struct. Biol, 3(3):233-239, 1996.
When developing a computational tool for the determination of favorable binding sites in molecules, according to the quantitative methods, it is possible to simulate intermolecular movement by computing intermolecular forces to determine a preferred "docking" site between the molecules. It is also possible to calculate the energy of interaction between the two molecules to determine as the best binding site those sites which have the most favorable or minimum potential energy. The predictive accuracy of any quantitative method is limited by the resolution or precision of the model. In most calculations, a grid is used onto which the molecule structures are mapped. This mapping takes place with or without some kind of transfer function, e.g. a 1/r-function in the case of electrostatic potential description. The calculation of the interaction between the two molecules, such as calculating the potential energy between the two molecules, must be done for each relative position of the two molecules, namely, each relative translational position and each rotational orientation between the two molecules. Since the amount of computation is extremely high, the prior art approach has been to select a moderate grid resolution before performing a calculation of favorable binding sites between molecules.